The overall goal of this project is to establish new animal models that will reliably predict the efficacy and safety of human immunodeficiency (HIV-1) vectors in humans. A major impediment to achieving this goal are the species-specific restriction on HIV-1 infectivity. These species- specific restrictions occur at a post-entry level and therefore apply to HIV-1 lentiviral vectors pseudotyped with heterologous envelope glycoproteins. An understanding of the HIV-1 genomic determinants of these restrictions will allow the creation of HIV-1 vectors that are suitable for infection of commonly used non-human primates. The insights obtained in this study will assist the establishment of new animal models of HIV-1 infection and the testing of HIV-1 vectors. The specific aims of the proposal are: 1) To adapt HIV-1 to replicate in monkey cell lines that exhibit progressively greater degrees of restriction against HIV-1 infection. 2) To characterize the changes in the adapted HIV-1 that are necessary and sufficient for replication in monkey cell lines. 3) To determine whether the adaptation-associated changes overcome the restrictions to HIV-1 infection in primary monkey cells and in some non- primate mammalian species. 4) To provide research-grade HIV-1 vectors to other investigators within the program.